title: A complex chromosome rearrangement involving four chromosomes, nine breakpoints and a cryptic 0.6-Mb deletion in a boy with cerebellar hypoplasia and defects in skull ossification.
abstract: Constitutional complex chromosomal rearrangements (CCRs) are considered rare cytogenetic events. Most apparently balanced CCRs are de novo and are usually found in patients with abnormal phenotypes. High-resolution techniques are unveiling genomic imbalances in a great percentage of these cases. In this paper, we report a patient with growth and developmental delay, dysmorphic features, nervous system anomalies (pachygyria, hypoplasia of the corpus callosum and cerebellum), a marked reduction in the ossification of the cranial vault, skull base sclerosis, and cardiopathy who presents a CCR with 9 breakpoints involving 4 chromosomes (3, 6, 8 and 14) and a 0.6-Mb deletion in 14q24.1. Although the only genomic imbalance revealed by the array technique was a deletion, the clinical phenotype of the patient most likely cannot be attributed exclusively to haploinsufficiency. Other events must also be considered, including the disruption of critical genes and position effects. A combination of several different investigative approaches (G-banding, FISH with different probes and SNP array techniques) was required to describe this CCR in full, suggesting that CCRs may be more frequent than initially thought. Additionally, we propose that a chain chromosome breakage mechanism may have occurred as a single rearrangement event resulting in this CCR. This study demonstrates the importance of applying different cytogenetic and molecular techniques to detect subtle rearrangements and to delineate the rearrangements at a more accurate level, providing a better understanding of the mechanisms involved in CCR formation and a better correlation with phenotype.
authors.affiliation: Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: R S
authors.initials: RS
authors.lastname: Guilherme
authors.forename: M C S P
authors.initials: MC
authors.lastname: Cernach
authors.forename: T E
authors.initials: TE
authors.lastname: Sfakianakis
authors.forename: S S
authors.initials: SS
authors.lastname: Takeno
authors.forename: L M M
authors.initials: LM
authors.lastname: Nardozza
authors.forename: C
authors.initials: C
authors.lastname: Rossi
authors.forename: S S
authors.initials: SS
authors.lastname: Bhatt
authors.forename: T
authors.initials: T
authors.lastname: Liehr
authors.forename: M I
authors.initials: MI
authors.lastname: Melaragno
mesh_terms: D002531:Cerebellum / Q000002:abnormalities*; D002869:Chromosome Aberrations; D002871:Chromosome Banding; D019457:Chromosome Breakage; D002872:Chromosome Deletion; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics; D015321:Gene Rearrangement; D006801:Humans; D007223:Infant; D007621:Karyotyping; D008297:Male; D009421:Nervous System Malformations / Q000235:genetics*; D012886:Skull; D014178:Translocation, Genetic